Cell and animal studies have indicated that changes in gene expression in the brain play an important role in the development of tolerance, dependence and neurotoxicity produced by long-term alcohol abuse. However, demonstrating that changes in gene expression indeed affect the behavioral response to ethanol remains a time- and labor- intensive proposition in mammals. We propose to use Drosophila as a model system to study the molecular mechanisms underlying the development of chronic ethanol tolerance. The fruit fly, with its powerful genetic techniques, has been used to study various aspects of drug-induced behaviors including ethanol, cocaine and nicotine sensitivity, cocaine sensitization and ethanol tolerance. Here we propose to take a phenotype-driven approach using genome-wide microarray profiling, to identify genes that play a central role in the behavioral changes induced upon .chronic ethanol exposure. In order to relate these transcriptional changes to behavior, we will generate mutations in selected genes identified by our microarray studies and analyze these mutants for altered drug-induced behaviors. The identification of molecular changes resulting from chronic ethanol exposure and the correlation of these changes with behavior will provide novel insights into the neurobiology of drug addiction.